Synthesis of some novel 2-anilinothiophene, 2,3′-bithienyl and thienylthiopyridine derivatives resistance to penicillium digitatum effect the fruit

Article abstract of DOI:10.1002/jccs.200700179

Reaction of benzotriazol-1-yl acetone 1 with phenyl isothiocyanate followed with α-chloroacetone or ethyl-α-chloroacetate afforded 2-anilinothiophenes 3 or 4, respectively. Treatment of 3 with malononitrile at different reaction conditions afforded 6 or 7

Full text of DOI:10.1002/jccs.200700179

Journal of the Chinese Chemical Society, 2007, 54, 1269-1276
1269
Synthesis of Some Novel 2-Anilinothiophene, 2,3¢-Bithienyl and
Thienylthiopyridine Derivatives Resistance to Penicillium Digitatum Effect
the Fruit
Fatima Al-Omran* and Adel Abou El-Khair
Chemistry Department, Kuwait University, Faculty of Science, P. O. Box 5969, 13060 Safat, Kuwait
Reaction of benzotriazol-1-yl acetone 1 with phenyl isothiocyanate followed with a-chloroacetone or
ethyl-a-chloroacetate afforded 2-anilinothiophenes 3 or 4, respectively. Treatment of 3 with malononitrile
at different reaction conditions afforded 6 or 7. Reaction of 1 with CS2 in DMF and phenacylbromide af-
forded S-alkylated thiophene 10. Reactions of the latter compound with different active methylene nitriles
afforded thienylthiopyridine derivatives 14 and 15. Condensation of 10 with hydrazine hydrate afforded
hydrazon derivative 16. Reaction of thiophene 17 with formamide in DMF afforded 19 which converted to
N-thienylpyrimidine 20 when treated with malononitrile. The structure of the newly synthesized com-
pounds has been established on the basis of their analytical and spectral data. The compounds were also in-
vestigated for antibacterial and antifungal activities.
Keywords: Thiophenes; Bithienyl; Thienylthiopyridone; Pyrimidine.
INTRODUCTION
RESULTS AND DISCUSSION
Pharmacological studies of thiophenes and their fused
derivatives have been shown to possess a variety of phar-
macological activities, such as in anticonvulsant agents1
and antirheumatic drugs.2 In fact, they are also known to be
human GnRH receptor antagonists used to treat reproduc-
tive diseases3 and have been used in the treatment of proto-
zoal parasitic diseases.4 Recently certain fused derivatives
were prepared as anti-inflammatory agents, particularly for
treating arthritis and as bone resorption inhibiting agents.5
4-Arylthiopyridine derivatives were prepared related to
non-nucleoside RT inhibitors of HIV-1.6 Promoted by
these observations and in continuation of our interest in the
design and synthesis of polyheterocyclic systems, particu-
larly those containing a thiophene nucleus,7-10 it was con-
sidered worthwhile to synthesize compounds bearing a
thiophene nucleus linked directly to thiophene or to thieno-
[2,3-b]pyridine, or to pyridine nuclei through an S linkage.
Only a limited number of molecules where an S atom links
pyridine to phenyl moieties has been described6 in the liter-
ature but not to thienyl moieties. We undertook the synthe-
sis of the title compounds which may show good biologi-
cal, medical and agricultural applications.
Treatment of benzotriazol-1-acetone 1 with phenyl
isothiocyanate in N,N-dimethylformamide (DMF) contain-
ing potassium hydroxide afforded the insoluble intermedi-
ate salt 2. The latter reacted in situ with an equimolar
amount of different alkylating agents, namely a-chloroace-
tone or ethyl-a-chloroacetate, afforded in each case 2-ani-
linothiophene derivataives 3 or 4, respectively, in good
yield (Scheme I). The 5-acetyl-2-anilinothiophene 3 proved
to be a useful key intermediate in the synthesis of several
heterocyclic nuclei. Thus, when 3 was treated with an equi-
molar amount of malononitrile in ethanolic piperidine solu-
tion at a refluxed temperature, it afforded a single product
6. The formation of the latter compound was considered to
proceed via the intermediacy of Knovengel condensation 5
with spontaneous intramolecular cyclization via a Michael
type electrophilic addition of its methyl group to the neigh-
bouring CN group (Scheme I). Similar phenomena have
been previously reported.12-13
In a continuation of our efforts to generate new syn-
thetic routes to different polyfunctional thiophenes,7-11 we
have used Gewald’s reaction14 for the synthesis of 2,3¢-
bithienyl derivative 7. The latter compound was obtained
* Corresponding author. E-mail: chesc@kuc01.kuniv.edu.kw or falomran@kuc01.kuniv.edu.kw

1270 J. Chin. Chem. Soc., Vol. 54, No. 5, 2007
Al-Omran and El-Khair
Scheme I
in situ via a one step process by treatment of 3 with mal-
ononitrile in the refluxing of ethanol and N,N-dimethyl-
formamide mixture with the presence of elemental sulfur
and a catalytic amount of triethylamine. The structure of 7
was established on the basis of elemental analysis and spec-
tral data. Notably a literature survey revealed that polythio-
phenes appear to be good candidates due to their organic
conducting polymers.15
again the 1H NMR spectrum of the reaction product was
found to have an ethyl group as triplet and quartet at dH 1.25
and 4.26 ppm with J = 7 Hz (Scheme I).
On the other hand, treatment of 1 with carbon disul-
fide in N,N-dimethylformamide solution (DMF) contain-
ing potassium hydroxide and subsequent treatment of the
reaction mixture with two molar amount of phenacylbro-
mide in situ afforded the S-alkylated thiophene 10. The 13
C
The 2,3¢-bithienyl derivative 7 underwent nucleo-
philic addition with benzylidenemalononitrile in refluxing
pyridine to afford the thieno[2,3-b]pyridine derivatives 8 in
good yield. The structure of 8 was confirmed on the basis of
elemental analysis and spectral data. The formation of 8 is
assumed to occur via initial formation of the Michael addi-
tion of the amino group in 7 to activate the double bond in
benzylidenemalononitrile followed by intramolecular
cyclization, then it loses hydrogen cyanide to afford the
thieno[2,3-b]pyridine derivative 89,11,16 (Scheme I).
Reaction of compound 4 with hydrazine hydrate in
boiling ethanol and N,N-dimethylformamide mixture in an
attempt to transform the ester group in compound 4 into
acid hydrazide function 9 was unsuccessful; however,
NMR data of 10 shows two low field signals at dC 189 and
194 ppm. The signal at approx. dC 189 corresponds to the
conjugated carbonyl carbon (CO) while that at dC 194 cor-
responds to carbonyl carbon bonded to methylene group
(SCH2CO); in addition, the high field signal d 45 ppm cor-
responds to the SCH2 group. The activated methylene group
in 10 readily takes part in numerous reactions providing
more complex molecules. Reaction of 10 with benzyli-
denemalononitrile in refluxing pyridine afforded 14. The
formation of 14 is assumed to take place via the initial Mi-
chael addition of active methylene of 10 to an activated
double bond in benzylidenemalononitrile yielding 11 that
then subsequently cyclizes to 12. The latter intermediate
undergoes Dimorth type rearrangement to 13 which aro-

Synthesis of Some Novel 2-Anilinothiophene
J. Chin. Chem. Soc., Vol. 54, No. 5, 2007 1271
matizes to 14 via loss of a hydrogen molecule. The 13C
NMR data of compound 14 shows two signals at approx. dC
150 and dC 188 ppm corresponding to the amide carbonyl
and conjugated carbonyl carbon, respectively, while the
signal corresponding to the methylene group was not ob-
served (Scheme II).
H-4 of the pyridine ring. Moreover, the 13C NMR spectrum
of the reaction product revealed two low field signals at dC
145 and 188.6 ppm corresponding to amide carbonyl and
conjugated carbonyl carbon, respectively. Treatment of
compound 10 with hydrazine hydrate in a mixture of etha-
nol and N,N-dimethylformamide at reflux temperature af-
forded 2¢-hydrazon derivative 16 (Scheme III).
Condensation of 10 with N,N-dimethylformamide
dimethylacetal (DMF DMA) in refluxing dioxan and then
subsequent treatment of the reaction mixture in situ with
malononitrile afforded the pyridine derivative 15. The
structure of 15 was established on the basis of its elemental
analysis and spectral data. For example, the 1H NMR showed
a resonance at approximately 8.15 ppm corresponding to
Compound 17 was readily prepared according to a re-
cently described procedure.11 Treatment of the latter com-
pound with formamide in refluxing N,N-dimethylform-
amide (DMF) produce either 4-aminothieno[2,3-d]pyrimi-
dine 18 or 19. In fact, only a single product was obtained;
structure 18 was ruled out on the basis of its elemental anal-
Scheme II

1272 J. Chin. Chem. Soc., Vol. 54, No. 5, 2007
Al-Omran and El-Khair
Scheme III
Scheme IV
ysis and spectral data. The presence of the cyano group ab-
sorption in the IR spectrum of the product indicates that the
cycano group is not involved in the reaction (Scheme IV).
Treatment of compound 19 with malononitrile in refluxing
ethanol and in the presence of a catylatic amount of piperi-
dine gave 3-thien-2-yl-pyrimidine derivative 20.

Synthesis of Some Novel 2-Anilinothiophene
J. Chin. Chem. Soc., Vol. 54, No. 5, 2007 1273
ture, then poured into ice-cold water and neutralized with
HCl (10%). The solid product so formed was collected by
filtration and recrystallized from the proper solvent.
Table 1. In vitro bactericidal and fungicidal activities of newly
synthesized compounds
Compound
B-subtilis
E-colic P-digitalum A-niger
6
++
+
++
+
-
++
++
++
+++
-
+
-
5-Acetyl-2-anilino-3-benzotriazol-1-yl-4-methylthio-
phene (3)
7
10
15
16
20
++
-
-
-
-
This compound was recrystallized from EtOH as
brown crystals, 2.86 g (83%), mp. 157-159 °C, IR: n = 3274
(NH), 1633 (keto CO) cm-1. 1H NMR (DMSO-d6): dH 1.97
(s, 3H, CH3), 2.15 (s, 3H, COCH3), 7.04-8.20 (m, 9H, Ar-
H), 9.25 ppm (br.s, 1H, NH, D2O-exchangeable). 13C NMR
(DMSO-d6): dC 19.6 (CH3), 30.1 (COCH3), 111.3, 116.8,
119.4, 120.7, 124.7, 125.7, 126.2, 129.5, 130.4, 135.2,
142.3, 146.0, 151.9, 152.8 (aromatic carbons) 190.1 ppm
(keto CO). Anal. Calcd. for C19H16N4OS (348.35): C,
65.51; H, 4.63; N, 16.08; S, 9.20%. Found: C, 65.37; H,
4.75; N, 16.05, S, 9.10.
-
-
-
-
-
+
-
Slight effect = +; Moderate effect = ++; Strong effect = +++
BIOLOGICAL ACTIVITY
The biological activities of some of the newly synthe-
sized compounds were screened for antifungal activity
against Aspergillus niger and Penicillium digitatum while
the antibacterial activity was tested against Escherichia
coli and Bacillus subtilis. Most of the test samples showed
bacterial and fungicidal activity (Table 1), especially to the
fungus Penicillium digitatum which affect fruit. These
fungus cause decay in fruit and then it becomes soft and
shrinks.
Ethyl-2-anilino-3-benzotriazol-1-yl-4-methylthiophene-
5-carboxylate (4)
This compound was recrystallized from EtOH as yel-
low crystals, 2.5 g (67%) mp. 146-148 °C. IR: n = 3239
(NH), 1702 (ester CO) cm-1. 1H NMR (DMSO-d6): dH 1.25
(t, 3H, J = 7 Hz, CH3), 2.01 (s, 3H, CH3), 4.26 (q, 2H, J = 7
Hz, CH2), 7.01-8.17 (m, 9H, Ar-H), 9.18 ppm (br.s, 1H,
NH, D2O exchangeable). Anal. Calcd. for C20H18N4O2S
(378.38): C, 63.48; H, 4.80; N, 14.81%. Found: C, 63.45;
H, 4.67; N, 14.88.
EXPERIMENTAL SECTION
All melting points are uncorrected. IR spectra (KBr)
were recorded on a Perkin Elmer 2000 FT-IR spectropho-
tometer. 1H NMR and 13C NMR spectra were recorded on a
Bruker 400 MHz spectrometer in dimethyl-d6-sulfoxide as
solvent and tetramethylsilane TMS as internal standard;
chemical shifts are reported as d units (ppm). Mass spectra
were measured on GS/MS VG Autospec Q instrument.
Microanalyses were performed on a LECO CHNS 932 ana-
lyzer. Compound 17 was prepared according to the litera-
ture.11
6-Acetamido-5-amino-2-anilino-3-benzotriazol-1-yl-7-
methyl benzo[b]thiophene (6)
To a stirred solution of 3 (3.48 g, 10 mmol) in EtOH
(20 mL) were added malononitrile (0.66 g, 10 mmol) and a
few drops of piperidine. The reaction mixture was refluxed
for 2 h, then left to cool at room temperature. The solid
product so formed was collected by filtration and recrys-
tallized from EtOH as off-white crystals, 2.73 g (66%), mp.
170-172 °C. IR: n = 3448-3179 (2NH2 & NH), 1588 (amide
CO) cm-1. 1H NMR (DMSO-d6): dH 2.36 (s, 3H, CH3), 5.20
(br.s, 2H, NH2 D2O exchangeable), 7.26-8.17 (m, 10H,
Ar-H), 10.69 (br.s, 2H, NH2, D2O exchangeable), 12.35
ppm (br.s, 1H, NH, D2O exchangeable). 13C NMR (DMSO-
d6) dC 20.44 (CH3), 110.7, 111.2, 113.6, 120.3, 120.7,
124.1, 125.2, 127.5, 127.9, 128.1, 128.6, 129.6, 129.8,
129.9, 136.0, 139.2, 139.8, 146.4 (aromatic carbons), 174.9
ppm (amide CO). Anal. Calcd. for C22H18N6OS (414.41):
C, 63.76; H, 4.38; N, 20.38%. Found: C, 63.48; H, 4.65; N,
Reaction of 1-Benzotriazolylacetone with a-Chloro-
acetone or Ethyl a-Chloroacetate (3-4)
General Procedure
A solution of 1 (1.75 g, 10 mmol), phenyl isothiocya-
nate (1.35 g, 10 mmol) and potassium hydroxide (0.56 g, 10
mmol) in DMF (20 mL) was stirred for 8 h at room temper-
ature. To a stirred solution, either a-chloroacetone or ethyl-
a-chloroacetate (10 mmol) was added and refluxed for 3 h.
The reaction mixture was allowed to cool at room tempera-

1274 J. Chin. Chem. Soc., Vol. 54, No. 5, 2007
Al-Omran and El-Khair
20.12.
mmol) in DMF (20 mL) was stirred for 10 h at room tem-
perature. To the stirred solution, phenacylbromide (0.98 g,
20 mmol) was added, then refluxed for 6 h. The reaction
mixture was allowed to cool at room temperature, then neu-
tralized with HCl (10%). The solid product so formed was
collected by filtration and recrystallized from EtOH: DMF
(2:1, v/v) as brown crystals 3.71 g (82%), mp. 75-77 °C. IR:
n = 1679 (COCH2), 1639 (COPh) cm-1. 1H NMR (DMSO-
d6): dH 1.94 (s, 3H, CH3), 4.85 (s, 2H, SCH2), 7.40-8.21
ppm (m, 14H, benzotriazolyl & phenyl-H). 13C NMR
(DMSO-d6): dC 15.2 (CH3), 44.7 (CH2), 111.6, 120.82,
125.8, 128.9, 129.2, 129.4, 129.5, 129.7, 129.8, 129.9,
130.0, 130.4, 130.5, 133.9, 134.2, 135.0, 139.5, 145.8 (aro-
matic carbons), 188.7 (COPh), 194.2 ppm (COCH2). Anal.
Calcd for C26H19N3O2S2 (469.45): C, 66.52; H, 4.07; N,
8.95; S, 13.60%. Found: C, 66.33; H, 4.31; N, 9.04; S,
13.50.
2-(5¢-Amino-4¢-cyanothien-3¢-yl)-5-anilino-4-benzotri-
azol-1-yl-3-methylthiophene (7)
A solution of 3 (3.48 g, 10 mmol), malononitrite (0.66
g, 10 mmol) and the element sulfur (0.32 g, 10 mmol) in a
mixture of EtOH : DMF (2:1, v/v) containing Et3N (1.0
mL) was refluxed for 3 h. The reaction mixture was left to
cool at room temperature. The solid product so formed was
collected by filtration and recrystallized from EtOH : DMF
(2:1, v/v) as brown crystals, 240 g (69%), mp. 194-201°C.
IR: n = 3266-3435 (NH2 & NH), 2209 (CN) cm-1. 1H NMR
(DMSO-d6): dH 1.97 (s, 3H, CH3), 6.99 (s, 1H, H-2¢, thienyl-
H), 7.17-8.18 (m, 9H, Ar-H), 8.20 (br s, 2H, NH2, D2O ex-
changeable), 9.25 ppm (br s, 1H, NH, D2O exchangeable).
13C NMR (DMSO-d6): dC 14.7 (CH3), 111.2, 116.7, 119.4,
120.7, 120.3, 120.5, 120.6, 121.1, 124.7, 125.5, 128.3,
129.7, 130.4, 130.5, 141.8, 142.5, 144.9, 145.9, 153.13
ppm (aromatic carbons). Anal. Calcd. for C22H16N6S2
(428.40): C, 61.68; H, 3.76; N, 19.62%. Found: C, 61.88;
H, 3.91; N, 19.92.
3-Cyano-1,2-dihydro-2-oxo-4,6-diphenyl-5-thio-[3¢-ben-
zotriazol-1-yl-5¢-benzoyl-4-methylthien-2¢-yl]pyridine
hydrochloride (14)
To a stirred solution of 10 (4.71 g, 10 mmol) in pyri-
dine (20 mL), benzylidenemalononitrile (1.54 g, 10 mmol)
was added and refluxed for 5 h. The reaction mixture was
allowed to cool at room temperature, then poured into ice-
cold water and neutralized with HCl (10%). The precipitate
was collected by filtration and recrystallized from DMF :
EtOH (1:2, v/v) as brown crystals, 4.07 g (62%), mp.
112-114 °C. IR: n = 3365 (NH), 2224 (CN), 1642 (keto
CO), 1593 (amide CO) cm-1. 1H NMR (DMSO-d6): dH 1.94
(s, 3H, CH3), 8.20 (br.s, 1H, NH D2O exchangeable), 7.48-
7.87 ppm (m, 19H, benzotriazolyl & phenyl-H). 13C NMR
(DMSO-d6): dH 19.5 (CH3), 115.8, 115.9, 125.4, 127.8,
129.1, 130.5, 130.6, 131.9, 133.2, 133.5, 133.8, 134.4,
134.6, 135.2, 136.9, 137.7, 137.8, 138.4, 138.8, 138.9,
140.1, 141.9, 143.4, 143.6, 146.2, 148.3, 148.5 (aromatic
carbons & CN), 150.2 (amide CO), 188.0 ppm (keto CO).
Anal. Calcd. for C36H24N5O2S2Cl (657.82): C, 65.73; H,
3.67; N, 10.62%. Found: C, 65.85; H, 3.77; N, 10.72.
4-Amino-3-(5¢-anilino-4¢-benzotriazol-1-yl-3¢-methyl-
thion-2¢-yl)-5-cyano-6-phenylthieno[b]pyridine hydro-
chloride (8)
A mixture of 7 (3.48 g, 10 mmol) and benzylidene-
malononitrile (1.54 g, 10 mmol) in pyridine (20 mL) was
refluxed for 3 h. The reaction mixture was then allowed to
cool at room temperature. The solid product so formed was
collected by filtration and recrystallized from EtOH : DMF
(2:1, v/v) as brown crystals, 3.11 g (71%) mp. 188-190 °C.
IR: n = 3264-3435 (NH2 & NH), 2209 (CN) cm-1. 1H NMR
(DMSO-d6): dH 1.97 (s, 3H, CH3), 7.03 (s, 1H, H-2, thienyl-
H), 7.20-8.14 (m, 14H, Ar-H), 8.20 (br.s, 2H, NH2 D2O ex-
changeable), 9.25 ppm (br.s, 1H, NH, D2O exchangeable).
13C NMR (DMSO-d6); dC 15.4 (CH3), 111.4, 116.8, 120.2,
120.5, 120.6, 120.7, 121.2, 123.2, 125.2, 125.4, 125.5,
129.4, 129.5, 129.6, 130.0, 130.1, 130.5, 132.1, 135.2,
135.5, 135.6, 141.1, 142.3, 146.0, 148.0, 152.8 ppm (aro-
matic carbons). Anal. Calcd. for C31H22N7S2Cl (591.98): C,
62.89; H, 3.74; N, 16.56; S, 10.81%. Found: C, 63.19; H,
4.05; N, 16.65; S, 10.73.
3-Cyano-1,2-dihydro-2-oxo-6-phenyl-5-thio(3¢-benzo-
triazol-1-yl-5¢-benzoyl-4¢-methylthien-2¢-yl]pyridine
hydrochloride (15)
3¢-Benzotriazol-1-yl-5¢-benzoyl-4¢-methylthien-2¢-yl-
thioacetophenone (10)
To a stirred solution of 10 (4.71 g, 10 mmol) in dioxan
(20 mL), DMF DMA (1.33 g, 10 mmol) was added. The re-
action mixture was refluxed for 3 h, then left to cool at
room temperature. To the refluxed mixture, a solution of
A solution of 1 (1.75 g, 10 mmol), carbon disulfide
(0.76 g, 10 mmol) and potassium hydroxide (0.56 g, 10

Synthesis of Some Novel 2-Anilinothiophene
J. Chin. Chem. Soc., Vol. 54, No. 5, 2007 1275
malononitrile (0.66 g, 10 mmol) in EtOH (20 mL) contain-
ing piperidine (1.0 mL) was added. The reaction mixture
was refluxed for 2 h, then allowed to cool at room tempera-
ture and poured into ice cold water. The solid product so
formed was collected by filtration and recrystallized from
EtOH as brown crystals, 4.01 g, (69%); mp. 90-92 °C, IR: n
= 3319 (NH), 2200 (CN), 1639 (keto CO) and 1596 (amide
7.28-7.95 (m, 5H, phthalimide-H & methylenic-H), 8.03
ppm (br.s, 2H, NH2, D2O exchangeable). Anal. Calcd. for
C15H10N4O2S (310.26): C, 58.06; H, 3.24; N, 18.04%.
Found: C, 58.03; H, 3.52; N, 17.85.
6-Amino-3-(3¢-cyano-4¢-phthalimidomethylthien-2¢-yl)-
3,4-dihydro-4-oxopyrimidine (20)
1
CO) cm-1. H NMR (DMSO-d6): dH 1.97 (s, 3H, CH3),
A mixture of 19 (3.20 g, 10 mmol) and malononitrile
(0.66 g, 10 mmol) in EtOH (20 mL) containing a few drops
of piperidine was refluxed for 2 h. The solid product so
formed was collected by filtration and recrystallized from
EtOH : DMF (2:1 v/v) as brown crystals, 2.60 g (69%); mp.
190-192 °C. IR: n = 3323-3198 (NH2), 2208 (CN), 1772
7.46-8.10 (m, 14H, Ar-H), 8.15 (s, 1H, H-4, pyridine-H),
8.22 ppm (br.s, 1H, NH, D2O exchangeable). 13C NMR
(DMSO-d6): dC 18.7 (CH3), 111.2, 111.5, 120.8, 125.9,
127.8, 128.9, 129.4, 129.6, 129.8, 130.1, 130.3, 130.4,
132.0, 133.7, 133.9, 134.3, 134.6, 135.5, 137.6, 138.8,
139.0, 141.7, 143.1 (aromatic carbons), 145.7 (amide CO),
188.6 ppm (keto CO). Anal. Calcd. for C30H20N5S2O2Cl
(581.96): C, 61.91; H, 3.46; N, 12.03%. Found: C, 62.03;
H, 3.60; N, 12.09.
1
and 1716 (phthalimide CO), 1635 cm-1 (amide CO). H
NMR (DMSO-d6): 4.79 (s, 2H, CH2), 7.23 (s, 1H, H-5,
thienyl-H), 7.68-8.36 (m, 8H, Ar-H & NH2). 13C NMR
(DMSO-d6): dC 41.7 (CH2N); 115.9, 117.0, 124.4, 124.6,
132.6, 134.5, 135.1, 135.6, 136.0, 146.7, 154.0 (aromatic
carbons), 164.9 (amide CO), 168.4 ppm (phthalimide CO).
Anal. Calcd. for C18H11N5O3S (377.31): C, 57.29; H, 2.93;
N, 18.56%. Found: C, 57.28; H, 3.01; N, 18.41.
3-Benzotriazol-1-yl-5-benzoyl-4-methyl-2-thio(ethyl-2¢-
hydrazono-2¢-phenyl)thiophene hydrochloride (16)
To a stirred solution of 10 (4.71 g, 10 mmol) in a mix-
ture of EtOH : DMF (1:1, v/v), hydrazine hydrate (0.5 g, 10
mmol) was added. The reaction mixture was refluxed for 1
h, then allowed to cool at room temperature and neutralized
with HCl (10%). The precipitate was collected by filtration
and recrystallized from EtOH:DMF (2:1, v/v) as brown
crystals, 3.68 g (71%), mp. 102-104 °C. IR: 3314-3434
(NH2), 1645 (keto CO) cm-1. 1H NMR (DMSO-d6): dH 2.0
(s, 3H, CH3), 4.89 (s, 2H, CH2), 7.28-7.90 ppm (m, 14H,
Ar-H), 8.12 (br.s, 2H, NH2, D2O exchangeable). 13C NMR
(DMSO-d6): dC 15.2 (CH3), 31.8 (CH2), 111.2, 111.6,
120.8, 125.8, 127.8, 129.2, 129.3, 129.4, 129.8, 130.0,
130.1, 130.3, 134.2, 134.4, 136.4, 139.1, 141.8, 145.6 (aro-
matic carbons), 163.3 (C=NNH2), 188.0 ppm (keto CO).
Anal. Calcd. For C26H22N5OS2Cl (519.93): C, 60.06; H,
4.26; N, 13.46%. Found: C, 60.09; H, 4.21; N, 13.46.
BIOLOGICAL TESTING
The newly synthesized compounds were tested against
the specified microorganism using 400 mg/mL (w/v) solu-
tions in sterile dimethyl-d6-sulfoxide (DMSO). A solution
of the tested compound (1.0 mL) was poured aseptically in
a well of 6 mm diameter made by a Cork borer in the nutri-
ent agar (NA) medium for the bacterial test and Sabouraud’s
agar for the fungal test. After placing the same volume in
wells of all tested microorganisms, nutrient agar plates
were incubated at 37 °C for 48 h, and Sabouraud’s dextrose
agar (SDA) plates were incubated at 25 °C for 48 h. The ac-
tivities were expressed as inhibition zones (mm, diameter,
as clear areas) as antibacterial and antifungal effects. The
least concentration, which showed inhibitory effect on any
specific microorganism, was considered as the minimum
inhibitory concentration (MIC) which was determined us-
ing streptomycin (50 mg/mL) as the reference.
2-(Aminomethylenimino)-4-(phthalimidomethyl)-3-
cyanothiophene (19)
A mixture of 17 (2.83 g, 10 mmol) and formamide
(0.39 g, 10 mmol) in DMF (20 mL) was refluxed for 10 h.
The reaction was left to cool at room temperature. The solid
product so formed was collected by filtration and recrystal-
lized from DMF : EtOH (2:1 v/v) as brown crystals, 2.01 g
(65%), mp. 138-140 °C. IR: n = 3312-3394 (NH2), 2204
(CN), 1772, 1718 cm-1 (phthalmide CO). 1H NMR (DMSO-
d6): dH 4.88 (s, 2H, CH2N), 7.20 (s, 1H, H-5, thiophene-H),
ACKNOWLEDGEMENT
This work was financed by the University of Kuwait
research grant SC07/04. We are grateful to the Faculty of

1276 J. Chin. Chem. Soc., Vol. 54, No. 5, 2007
Al-Omran and El-Khair
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Science, Chemistry Department, SAF facility, for the spec-
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